Increased neutrophil count in peripheral blood, known as neutrophilia, often results from bacterial infection. Since neutrophils possess highly specialized bactericidal functions such as degranulation and superoxide production, an increase in the number of available neutrophils is beneficial to host defense and can facilitate the elimination of invading bacteria. Neutrophilia also results from noninfectious insults including trauma, malignancy, surgery and certain autoimmune diseases. Neutrophilia is one of the clinical signs of systemic inflammatory response syndrome, which often lacks a proven source of infection (Robertson and Coopersmith, 2006). An increase in the number of neutrophils can facilitate their tissue infiltration, contributing to tissue damage as seen in sterile inflammation and autoimmune diseases such as rheumatoid arthritis. Whereas the mechanisms by which bacterial infection causes neutrophilia have been clearly defined, the endogenous factors and pathways responsible for neutrophilia under noninfectious conditions remain to be characterized.
In response to inflammatory stimuli, neutrophils move from storage pools into blood circulation. This initial process is followed by mobilization of bone marrow reserves and expansion of pluoripotent marrow cells committed to granulocytic differentiation, which requires granulocyte colony-stimulating factor (G-CSF), a potent cytokine and hematopoietic growth factor (Demetri and Griffin, 1991). In resting state, the serum concentration of G-CSF is <40 pg/ml in healthy individuals. It increases by up to several hundred folds during acute infection and sepsis (Hareng and Hartung, 2002). G-CSF concentration also increases in response to noninfectious insults such as trauma, malignancy and surgery, collectively known as the acute-phase response
(Kushner and Rzewnicki, 1999). The association between neutrophilia and increased serum G-CSF level has been well documented. All leukocytes express G-CSF when challenged with exogenous stimuli such as LPS, LTA, phorbo 12-myristate 13-acetate (PMA), phytohaemagglutinin (PHA), endogenous cytokines and hematopoietic growth factors such as TNFα, IL-1β, IL-3, IL-17, GM-CSF and M-CSF (Demetri and Griffin, 1991; Hareng and Hartung, 2002). However, a causal relationship between increased acute-phase proteins, enhanced production of G-CSF and neutrophilia has not been established.
SAA is a major acute-phase protein of 104 amino acids whose concentration in plasma increases by up to 1.000-fold during acute-phase response (to trauma, infection and tissue injury) (Gabay and Kushner, 1999). A correlation between elevated SAA concentration and progression of inflammatory diseases such as arthritis, inflammatory bowel diseases and atherosclerosis has been reported (Chambers et al., 1983; Fyfe et al., 1997; Ma11e and De Beer, 1996). Despite the wide use of these biomarkers, the biological functions of SAA and CRP were not known until recently. Several published reports demonstrate that SAA has cytokine-like activity and can stimulate production of other cytokines by monocytes and macrophages (Furlaneto and Campa, 2000; Patel et al., 1998; Vallon et al., 2001). Studies have shown that SAA can induce the expression of proinflammatory cytokines such as IL-1β, TNFα, and IL-6, growth-stimulatory cytokines such as G-CSF, chemokines such as IL-8 and MCP-1, and immunomodulatory cytokines such as WL-12p40 and IL-23 (He et al., 2003; He et al., 2006). The known SAA receptors and binding partners are formyl peptide receptor-like 1 (FPRL1), scavenge receptor BI (SR-BI), Tanis, the integrin αIIbβ3, and heparin and heparan sulfate. These receptors and binding partners are not specialized in the induction of proinflammatory cytokines, although activation of some (e.g. FPRL1) can lead to gene expression. Therefore the receptor(s) responsible for SAA-induced proinflammatory cytokine expression remain to be identified.
The precise mechanism by which SAA regulates inflammation, however, remains unclear. Elucidating the role of SAA in inflammation and immunity and identifying the binding partners of SAA involved in inflammation and immunity should prove useful for identifying therapeutic targets for a variety of diseases.